- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01544491
Efficacy, Tolerability and Safety of Early Introduction of Everolimus, Reduced Calcineurin Inhibitors and Early Steroid Elimination Compared to Standard CNI, Mycophenolate Mofetil and Steroid Regimen in Paediatric Renal Transplant Recipients
A 12-month, Multicenter, Open Label, Randomized, Controlled Study to Evaluate the Efficacy, Tolerability and Safety of Early Introduction of Everolimus, Reduced CNI, and Early Steroid Elimination Compared to Standard CNI, Mycophenolate Mofetil and Steroid Regimen in Paediatric Renal Transplant Recipients With a 24-month Additional Safety Follow-up.
The purpose of this study is to determine if everolimus combined with reduced exposure CNI (TAC) is efficacious and safe and will support corticosteroid elimination compared to a standard exposure CNI (TAC) + MMF + steroid regimen after paediatric kidney transplantation. An additional purpose of the study is to assess the effect of the combination of EVR and reduced exposure CNI (TAC) on renal function.
This study is part of the requirements of the Paediatric Investigational Plan approved by Paediatric Committee at the European Medicines Agency (PDCO/EMA) on September 10, 2010, and is intended to support the indication of everolimus in the prevention of acute rejection in paediatric recipients of a renal transplant.
Study Overview
Status
Intervention / Treatment
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
-
-
-
Santa Fe, Argentina, S3000EPV
- Novartis Investigative Site
-
-
-
-
RS
-
Porto Alegre, RS, Brazil, 90020-090
- Novartis Investigative Site
-
-
SP
-
São Paulo, SP, Brazil, 04038-002
- Novartis Investigative Site
-
-
-
-
-
Bron Cedex, France, 69677
- Novartis Investigative Site
-
Lille, France, 59000
- Novartis Investigative Site
-
Paris, France, 75019
- Novartis Investigative Site
-
Paris cedex 15, France, 75015
- Novartis Investigative Site
-
-
-
-
-
Berlin, Germany, 13353
- Novartis Investigative Site
-
Essen, Germany, 45147
- Novartis Investigative Site
-
Hamburg, Germany, 20246
- Novartis Investigative Site
-
Hannover, Germany, 30625
- Novartis Investigative Site
-
Heidelberg, Germany, 69120
- Novartis Investigative Site
-
Muenster, Germany, 48149
- Novartis Investigative Site
-
Tübingen, Germany, 72076
- Novartis Investigative Site
-
-
-
-
-
Budapest, Hungary, 1082
- Novartis Investigative Site
-
-
-
-
BO
-
Bologna, BO, Italy, 40138
- Novartis Investigative Site
-
-
GE
-
Genova, GE, Italy, 16147
- Novartis Investigative Site
-
-
ITA
-
Roma, ITA, Italy, 00165
- Novartis Investigative Site
-
-
PD
-
Padova, PD, Italy, 35128
- Novartis Investigative Site
-
-
TO
-
Torino, TO, Italy, 10126
- Novartis Investigative Site
-
-
-
-
-
Oslo, Norway, 0424
- Novartis Investigative Site
-
-
-
-
-
Warsaw, Poland, 04 730
- Novartis Investigative Site
-
-
-
-
Barcelona
-
Esplugues de Llobregat, Barcelona, Spain, 08950
- Novartis Investigative Site
-
-
-
-
-
Stockholm, Sweden, 14186
- Novartis Investigative Site
-
-
-
-
-
Antalya, Turkey, 07070
- Novartis Investigative Site
-
-
-
-
-
London, United Kingdom, WC1N 1EH
- Novartis Investigative Site
-
Manchester, United Kingdom, M13 9WL
- Novartis Investigative Site
-
Nottingham, United Kingdom, NG7 2UH
- Novartis Investigative Site
-
-
-
-
California
-
Los Angeles, California, United States, 90095-1752
- Novartis Investigative Site
-
-
Michigan
-
Ann Arbor, Michigan, United States, 48109-0331
- Novartis Investigative Site
-
-
Missouri
-
Saint Louis, Missouri, United States, 63110
- Novartis Investigative Site
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Inclusion criteria at baseline:
- Written informed consent/assent must be obtained from the parent(s) or legal guardian before any assessment is performed.
- Primary or secondary paediatric kidney transplant recipient aged greater than or equal to 1 year and younger than 18 years receiving a deceased donor or non-HLA identical living donor (related or unrelated) renal transplant.
Inclusion criteria at randomization:
- Patients on TAC + MMF + steroids.
- Renal function with eGFR > 40 ml/min/1.73 m2 (Schwartz formula - abbreviated).
Exclusion Criteria:
Exclusion criteria at baseline:
- Recipients of kidneys from donors with known renal disease (such as diabetes nephropathy, nephrosclerosis), at the time of transplant.
- Recipients of a kidney with a cold ischemia time > 24 hours.
- History of hypersensitivity or contraindications to any of the study drugs or to drugs of similar chemical classes, or to any of the excipients.
- History of malignancy of any organ system treated or untreated, carrying possible risk of recurrence according to current guidelines (Appendix 10 of protocol).
Exclusion criteria at randomization:
- Use of other investigational drugs at the time of randomization, or within 30 days or 5 half-lives prior randomization, whichever is longer.
- Patients with ongoing or recently (within 2 weeks prior to randomization) treated episodes of acute rejection (any grade) or a steroid resistant acute rejection at the time of randomization.
- Patients who experienced acute cellular rejection (Banff ≥1B) or any antibody mediated acute rejection or patients considered at high risk of antibody mediated acute rejection by the investigator assessment (e.g. presence of newly formed DSA, histological suspicion) at any time before randomization (as the DSA quantitative threshold to define high risk is not fully established, the assessment of the risk will be made after discussion between the laboratory expert and the investigator who will take into account all information available and apply best judgment).
- Patients with ongoing wound healing problems, clinically significant wound infection requiring continued therapy or other severe surgical complication in the opinion of the investigator.
- Patients who are treated with drugs that are strong inducers or inhibitors of cytochrome P450 3A4 (CYP3A4) and can not discontinue the treatment (see Appendix 6 for list of medications).
- Patients with nephrotic range proteinuria (protein to creatinine ratio ≥2.0 mg/mg or 200 mg/mmol (Hogg, 2003).
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Investigational arm
Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant
|
Everolimus (C0 trough level of 3-8 ng/mL) in combination with reduced dose tacrolimus and steroids withdrawal at 6 months after transplant
|
Active Comparator: Control arm
MMF continuation (in combination with tacrolimus and standard dose steroids)
|
MMF (Cellcept®): 600mg/m2/dose twice daily (1200 mg/m2/day) in combination with tacrolimus (Prograf) and standard dose steroids
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants Having Reached the Composite Efficacy Endpoint of Biopsy-proven Acute Rejection
Time Frame: 12 months, 36 months
|
To estimate the rate of the composite efficacy endpoint of biopsy-proven acute rejection (BPAR), graft loss or death at 12 months post transplantation in primary paediatric kidney transplant recipients converted at 4-6 weeks post-transplantation from MMF + standard TAC regimen and steroids, to everolimus + reduced dose TAC regimen and steroid withdrawal at 6 months, versus continuation of MMF + standard TAC regimen and steroids.
|
12 months, 36 months
|
To Evaluate Renal Function, Assessed by Glomerular Filtration Rate (eGFR) and Estimated by the Schwartz Formula (Abbreviated), at Month 12 and 36
Time Frame: 12 months and 36 months post-transplantation
|
To evaluate renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Schwartz Formula (abbreviated) (Schwartz, 2009).
|
12 months and 36 months post-transplantation
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Composite Efficacy Endpoint
Time Frame: at 12 and 36 months post-transplantation
|
To evaluate the proportion of patients with the following efficacy events: Biopsy Proven Acute Rejection (BPAR), graft loss or death.
The efficacy events will be descriptively summarized by treatment group.
|
at 12 and 36 months post-transplantation
|
To Evaluate the Severity of BPAR (Acute T-cell Mediated Rejection Only) (Banff 2009)
Time Frame: month 12, month 36
|
T-cell mediated rejection severity : Type IA - Significant interstitial infiltration (> 25% of parenchyma) and foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IB - Significant interstitial infiltration (> 25% of parenchyma) and foci of severe tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IIA - Mild to moderate intimal arteritis Type IIB - Severe intimal arteritis comprising > 25% of the lumenal area Type III - Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation) |
month 12, month 36
|
To Evaluate the Time to Event of BPAR
Time Frame: 36 months
|
Time to incidence of Event, given in terms of number of participants with an Event according to time interval up to 36 months
|
36 months
|
Incidence of Biopsy Proven Antibody Mediated Rejection.
Time Frame: at 12 and 36 months post-transplantation
|
To evaluate the proportion of patients with the following efficacy events: biopsy proven antibody mediated rejection/Steroid resistant BPAR and BPAR treated with T cell depleting therapy.
|
at 12 and 36 months post-transplantation
|
Chronic Allograft Nephropathy / Interstitial Fibrosis and Tubular Atrophy
Time Frame: at 12 and 36 months post-transplantation.
|
To evaluate the proportion of patients with chronic allograft nephropathy (interstitial fibrosis and tubular atrophy, IF/TA) by histopathology and its progression.The term chronic allograft nephropathy was used inappropriately in the protocol and therefore, replaced by interstitial fibrosis and tubular atrophy
|
at 12 and 36 months post-transplantation.
|
Proteinuria (Urinary Protein/Creatinine Ratio)
Time Frame: at 12 and 36 months post-transplantation
|
The urinary protein/creatinine ratio will be descriptively summarized by treatment group at each visit.
The incidence rate of patients with proteinuria will be categorized in <0.2 g/mg/mg, 0.2<2.0
mg/mg and ≥ 2.0 mg/mg and summarized by treatment groups at each visit.
|
at 12 and 36 months post-transplantation
|
Growth/Development : Weight, Height, BMI : Change From Baseline
Time Frame: month 12 , month 36 post transplantation.
|
Evaluation of the potential effects upon the bone growth.
The Z-score is a statistical tool which helps to assess data (here child growth parameters) relative to a reference or standard population.
The Z-score describes the distance and direction of an observation away from the population median (or mean, however, here the median was used).
A negative Z-score shows that data are lower than the median of the standard population, a positive Z-score shows that data are higher than the median of the standard population, and a Z-score of zero shows that the data are equal to the median of the standard population.
The more the Z-score is distant from 0, the more expressed is for example underweight or overweight.
|
month 12 , month 36 post transplantation.
|
Evaluation of Evolution of Renal Allograft Function Over Time
Time Frame: baseline, 6 months, 12 months , 24 months, 36 months
|
results given as eGFR values by time interval
|
baseline, 6 months, 12 months , 24 months, 36 months
|
To Evaluate Renal Function, Assessed by Glomerular Filtration Rate (eGFR) and Estimated by the Schwartz Formula (Extended), at Month 12
Time Frame: 12 months post-transplantation
|
To evaluate renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Schwartz Formula (extended) (Schwartz, 2009).
Results given as change from randomization
|
12 months post-transplantation
|
Collaborators and Investigators
Sponsor
Publications and helpful links
General Publications
- Patry C, Sauer LD, Sander A, Krupka K, Fichtner A, Brezinski J, Geissbühler Y, Aubrun E, Grinienko A, Strologo LD, Haffner D, Oh J, Grenda R, Pape L, Topaloğlu R, Weber LT, Bouts A, Kim JJ, Prytula A, König J, Shenoy M, Höcker B, Tönshoff B. Emulation of the control cohort of a randomized controlled trial in pediatric kidney transplantation with Real-World Data from the CERTAIN Registry. Pediatr Nephrol. 2022 Oct 20. doi: 10.1007/s00467-022-05777-x. [Epub ahead of print]
- Tonshoff B, Tedesco-Silva H, Ettenger R, Christian M, Bjerre A, Dello Strologo L, Marks SD, Pape L, Veldandi U, Lopez P, Cousin M, Pandey P, Meier M. Three-year outcomes from the CRADLE study in de novo pediatric kidney transplant recipients receiving everolimus with reduced tacrolimus and early steroid withdrawal. Am J Transplant. 2021 Jan;21(1):123-137. doi: 10.1111/ajt.16005. Epub 2020 Jun 27.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- CRAD001A2314
- 2010-024381-21 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Prevention of Acute Rejection in Paediatric Recipients of a Renal Transplant
-
Wake Forest University Health SciencesStanford UniversityCompletedRenal Transplant | Rejection Acute Renal | Rejection Chronic Renal | Rejection of Renal Transplant | Renin-Angiotensin SystemUnited States
-
Ha Young OhBaxter Healthcare CorporationUnknownAcute Rejection of Renal Transplant | Delayed Function of Renal Transplant | Primary Nonfunction of Renal TransplantKorea, Republic of
-
Novartis PharmaceuticalsCompletedProphilaxis of Acute Rejection in Patients Receiving a Renal AllograftSpain
-
University of CincinnatiRoche Pharma AG; University of TennesseeCompletedAcute Allograft Rejection in Simultaneous Kidney/Pancreas Transplant RecipientsUnited States, Canada
-
Nova Scotia Health AuthorityCompletedAcute Rejection of Renal TransplantCanada
-
Seoul St. Mary's HospitalUnknownAcute Rejection of Renal TransplantKorea, Republic of
-
Icahn School of Medicine at Mount SinaiNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University... and other collaboratorsCompletedPediatric Recipients of a Liver TransplantUnited States
-
Universitaire Ziekenhuizen KU LeuvenCompletedAcute Rejection of Renal Transplant | Renal Graft LossBelgium
-
Loma Linda UniversityRecruitingGraft Failure | Acute Rejection of Renal TransplantUnited States
-
University of ManitobaCanadian Institutes of Health Research (CIHR); Canadian National Transplant...RecruitingKidney Transplant; Complications | Rejection of Renal TransplantAustralia, Canada
Clinical Trials on RAD001
-
Children's Hospital Medical Center, CincinnatiNovartisCompletedTuberous Sclerosis | AngiolipomaUnited States
-
Novartis PharmaceuticalsCompletedMetastatic Renal Cell Carcinoma (mRCC)Germany
-
University of Alabama at BirminghamNational Cancer Institute (NCI); Children's Hospital of Philadelphia; Washington... and other collaboratorsCompleted
-
Novartis PharmaceuticalsCompleted
-
Novartis PharmaceuticalsCompletedLymphangioleiomyomatosis (LAM) | Tuberous Sclerosis Complex (TSC)United States, United Kingdom, Germany, Italy, Russian Federation, Netherlands, Japan, Canada, Poland, France, Spain
-
Radiation Therapy Oncology GroupNational Cancer Institute (NCI); NRG OncologyCompletedBrain and Central Nervous System TumorsUnited States, Israel, Canada
-
University of ChicagoNovartis PharmaceuticalsTerminatedNon-Small Cell Lung CancerUnited States
-
Guangdong Provincial People's HospitalNovartisUnknownNeuroendocrine Tumors | Carcinoid TumorChina
-
Fox Chase Cancer CenterRecruitingMetastatic Pancreatic CancerUnited States
-
Novartis PharmaceuticalsTerminatedHepatocellular CarcinomaUnited States, Spain, Korea, Republic of, Netherlands, Taiwan